I am studying cancer genetics and the biology of leukemia, with the long term goal of identifying more specific and less toxic treatments for leukemia. I am interested in dissecting the role of individual mutations in leukemia, and understanding the minimum cellular changes required for leukemia formation. Expansion of myeloid blasts with suppression of normal hematopoiesis is the hallmark of acute myeloid leukemia (AML). In contrast, myelodysplastic syndromes (MDSs) are usually associated with low blood cell counts and aberrant bone marrow morphology, while myeloproliferative disorders (MPDs) are characterized by over-proliferation of one or more lineages that retain the capacity to differentiate. Importantly, many patients with MDS and MPD ultimately evolve into acute leukemia that is refractory to treatment. The acquired genetic lesions that mediate transformation from MDS/MPD to acute leukemia are largely unknown. Our laboratory has generated mouse models of MPD initiated by expression of oncogenic Kras or by inactivation of the Nf1 tumor suppressor gene, which encodes neurofibromin, a GTPase activating protein that negatively regulates Ras signaling. Neither strain spontaneously develops acute leukemia;however, in preliminary data, cooperating mutations provided by mutagenesis can mediate transformation to AML. This strategy represents a powerful system to identify genetic mutations and the cellular consequences that are important for the evolution of MPD to acute leukemia. The goals of my K08 proposal are to (1) identify genetic mutations that can cooperate with hyperactive Ras, (2) investigate the biochemical and genetic basis of response and resistance to MEK inhibition in Nf1 deficient AMLs and (3) investigate the contribution of Nf1 loss to growth and survival of leukemia. After performing forward genetic screens in Nf1 mutant mice, I will functionally characterize candidate leukemia genes and screen the human homologs of these genes in leukemias that have evolved in patients with MPD of MDS. I will evaluate the effect of restoring Nf1 function and perform comparative genetic, biochemical, and functional studies of primary cells from mice with MPD and AML. Acute myeloid leukemia arises in a variety of clinical settings, and is fatal for the majority of adults and children afflicted. The goal of this project is to model the multi-step process by which a normal cell transforms into leukemia. Improved understanding of these cellular changes will inform drug design and improve treatment and outcome for AML.